Despite decades of development of antidepressant treatments, even the most effective interventions often take weeks to achieve symptom relief, and are only effective in a subset of patients who try them. From 40 to 60% of patients with depression experience a rapid and significant improvement of mood with one night of total or partial sleep deprivation (SD). Although the antidepressant effect of SD has been known for decades, the neural mechanisms underlying this effect have not been elucidated. Recent advances in functional neuroimaging have provided new opportunities to investigate state changes in regional brain function, along with a better understanding of the neural networks affected by depression and SD. Previous depression studies from our group as well as others have consistently demonstrated dysfunction in brain networks underlying arousal, emotion regulation, and self-referential processing. Our neuroimaging data in healthy controls shows that SD can change the function of these same networks and these changes are opposite to that seen in depressed patients versus controls. Here we propose to study a group of N=48 antidepressant- free male and female patients with current depression symptom and N=12 healthy controls with no history of mood disorders before and after SD to provide mechanistic insight into the neural substrates underlying the antidepressant effects of SD. We hypothesize that SD-induced concurrent functional activity and connectivity changes in multiple brain networks related to different depressive symptom dimensions including emotion regulation, attention, arousal, self-referential, and reward processing will underlie the rapid and transient antidepressant effects of SD. Using an ABA design, multimodal brain imaging along with more traditional electroencephalographic (EEG) and neurobehavioral testing data will be acquired at baseline after normal sleep, during one night of total SD, and after one night of recovery sleep using a 5-day in laboratory protocol during which subjects will be continuously monitored by trained staff. An interdisciplinary team of researchers with expertise in depression, neuroimaging, sleep, and chronobiology will collaborate to carry out this project using state-of-the-art approaches. Results from this project will not only elucidate neural mechanisms underlying the rapid antidepressant effects of SD, but also yield brain-based biomarkers to predict or monitor individual responses to SD and potentially novel targets for pharmacological and neuromodulatory interventions.